Special Warning : אזהרת שימוש

5       WARNINGS AND PRECAUTIONS
5.1     Bronchospasm
RELENZA is not recommended for treatment of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease).
Serious cases of bronchospasm, including fatalities, have been reported during treatment with RELENZA in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess.
RELENZA should be discontinued in any patient who develops bronchospasm or decline in respiratory function; immediate treatment and hospitalization may be required.
Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions.

Bronchospasm was documented following administration of zanamivir in 1 of 13 subjects with mild or moderate asthma (but without acute influenza-like illness) in a Phase I trial. In a Phase III trial in subjects with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, 10% (24 of 244) of subjects on zanamivir and 9% (22 of 237) on placebo experienced a greater than 20% decline in FEV1 following treatment for 5 days.
If use of RELENZA is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. If a decision is made to prescribe RELENZA for such a patient, this should be done only under conditions of careful monitoring of respiratory function, close observation, and appropriate supportive care including availability of fast-acting bronchodilators.
5.2     Allergic Reactions
Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis have been reported in postmarketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected.
5.3     Neuropsychiatric Events
Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.
There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including RELENZA. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon based on usage data for RELENZA. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of RELENZA to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.
5.4     Limitations of Populations Studied
Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management.
5.5     Bacterial Infections
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RELENZA has not been shown to prevent such complications.


Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.


5.6     Importance of Proper Route of Administration
RELENZA Inhalation Powder must not be made into an extemporaneous solution for administration by nebulization or mechanical ventilation. There have been reports of hospitalized patients with influenza who received a solution made with RELENZA Inhalation Powder administered by nebulization or mechanical ventilation, including a fatal case where it was reported that the lactose in this formulation obstructed the proper functioning of the equipment.
RELENZA Inhalation Powder must only be administered using the device provided [see Dosage and Administration (2.1)].
5.7     Importance of Proper Use of DISKHALER
Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. Prescribers should carefully evaluate the ability of young children to use the delivery system if use of RELENZA is considered [see Use in Specific Populations (8.4)].

6       ADVERSE REACTIONS
See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm (5.1) and allergic-like reactions (5.2), and for safety information in patients with underlying airways disease (5.1).
6.1     Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The placebo used in clinical trials consisted of inhaled lactose powder, which is also the vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation.
Treatment of Influenza: Clinical Trials in Adults and Adolescents: Adverse events that occurred with an incidence 1.5% in treatment trials are listed in Table 1. This table shows adverse events occurring in subjects aged 12 years and older receiving RELENZA 10 mg inhaled twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA).


Table 1. Summary of Adverse Events 1.5% Incidence During Treatment in Adults and Adolescents
RELENZA
10 mg b.i.d.       All Dosing              Placebo
Inhaled         Regimens    a      (Lactose Vehicle)
Adverse Event                 (n = 1,132)       (n = 2,289)           (n = 1,520) Body as a whole
Headaches                                 2%                2%                     3% Digestive
Diarrhea                                  3%                3%                     4% Nausea                                    3%                3%                     3% Vomiting                                  1%                1%                     2% Respiratory
Nasal signs and symptoms                  2%                3%                     3% Bronchitis                                2%                2%                     3% Cough                                     2%                2%                     3% Sinusitis                                 3%                2%                     2% Ear, nose, and throat infections          2%                1%                     2% Nervous system
Dizziness                                 2%                1%                    <1% a
Includes trials where RELENZA was administered intranasally (6.4 mg 2 to 4 times per day in addition to inhaled preparation) and/or inhaled more frequently (q.i.d.) than the currently recommended dose.

Additional adverse reactions occurring in less than 1.5% of subjects receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.
The most frequent laboratory abnormalities in Phase III treatment trials included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness.
Clinical Trials in Pediatric Subjects: Adverse events that occurred with an incidence 1.5% in children receiving treatment doses of RELENZA in 2 Phase III trials are listed in Table 2. This table shows adverse events occurring in pediatric Subjects aged 5 to 12 years old receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA).


Table 2. Summary of Adverse Events 1.5% Incidence During Treatment in Pediatric Subjectsa
RELENZA                     Placebo
10 mg b.i.d. Inhaled       (Lactose Vehicle)
Adverse Event                       (n = 291)                 (n = 318) Respiratory
Ear, nose, and throat infections                5%                        5% Ear, nose, and throat hemorrhage               <1%                        2% Asthma                                         <1%                        2% Cough                                          <1%                        2% Digestive
Vomiting                                        2%                        3% Diarrhea                                        2%                        2% Nausea                                         <1%                        2% a
Includes a subset of subjects receiving RELENZA for treatment of influenza in a prophylaxis trial.

In 1 of the 2 trials described in Table 2, some additional information is available from children (aged 5 to 12 years) without acute influenza-like illness who received an investigational prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with RELENZA than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients.

6.2     Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of zanamivir (RELENZA). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zanamivir (RELENZA).
Allergic Reactions: Allergic or allergic-like reaction, including oropharyngeal edema [see Warnings and Precautions (5.2)].
Psychiatric: Delirium, including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares [see Warnings and Precautions (5.3)].
Cardiac: Arrhythmias, syncope.

Neurologic: Seizures. Vasovagal-like episodes have been reported shortly following inhalation of zanamivir.
Respiratory: Bronchospasm, dyspnea [see Warnings and Precautions (5.1)].
Skin: Facial edema; rash, including serious cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); urticaria [see Warnings and Precautions (5.2)].

Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@m oh.gov.il

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